X-ray contrast compounds



United States Patent X-RAY CONTRAST COMPOUNDS William Galler, ValleyStream, N. Y., asslgnor to American Cystoscope Makers, Inc, New York, N.Y., a corporation of New York No Drawing. Application July 16, 1953,Serial No. 368,518

12 Claims. (Cl. 260-501) The present invention relates to nuclearsubstituted hydroxyor amino-derivatives of halo-phenoxy-aliphaticcarboxylic acids and halo-phenylamino-aliphatic carboxylic acids.

It is the object of the present invention to provide new chemicalcompounds which are useful in the radiography of the internal organs,particularly in the urological tract.

Other objects of the invention will be apparent to those skilled in theart upon reading the specification which follows:

The compositions of this invention include water-soluble salts which maybe injected intravenously and orally and are collected by the kidney.The radiographs taken using such compounds in the urological tract aidin revealing normal and abnormal structures. These watersoluble saltsare readily excreted without increasing the burden upon the kidney.Moreover, these compositions have a low incidence of untoward elfects onthe patient. In addition to the utilization in the excretion radiographyof the kidney, the water-soluble salts may be used in making retrogradepyelographs; and because of this fact, they can be used for radiographyof other hollow organs, such as the sinuses. They may be administeredintravenously or orally.

The novel chemical compounds of this invention are nuclear substitutedhydroxyor amino-derivatives of halophenoxy-aliphatic carboxylic acids orhalo-phenylamino aliphatic carboxylic acids, and their non-toxic,watersoluble salts. The preferred compounds of the invention are thosehaving the following structural formula:

wherein X1 is a member selected from the class consisting of hydrogen,iodine and bromine; X: is a member selected from the class consisting ofbromine and iodine; Y is a member selected from the class consisting ofthe hydroxyl group, an amino group, monoand dilower alkyl substitutedamino groups; Z is a member selected from the class consisting of theoxygen atom and the N-I-I group; n is an integer from 1 to 5; and M is amember selected from the class consisting of hydrogen, thealkali-metals, the ammonium group, the alkylammonium andalltanolammonium groups. Best results have been obtained with the polyordiiodo-hydroxyphenoxyacetic acids and their water-soluble salts,particularly the sodium salts. It is more desirable to utilize compoundswhich are more highly halogenated, and especially those compounds havingmore than one iodine atom substituted on the benzene ring.

The halogens contemplated in my invention are bromine and iodine,especially the latter.

In the case of the hydroxyor amino-substituted halophenoxy-aliphaticcarboxylic acids, the starting materials 2,813,118 Patented Nov. 12,1957 for the production of the compounds of this invention are thecorresponding hydroxyor amino-substituted phenoxy-aliphatic carboxylicacids. When it is desired to prepare the hydroxyor amino-substitutedhalo-phenylamino-aliphatic carboxylic acids, the desired startingmaterial is the corresponding hydroxyor amino-substitutedphenylamino-aliphatic carboxylic acids. These starting materials arewell known to those familiar with this art. The starting material isconverted to the desired halogenated compounds of the invention bytreatment with an appropriate halogenating agent, such as bromine, or amixture of iodine and potassium iodide, or preferably such iodinationagents as iodine monochloride. The resulting halogenated acids arerelatively insoluble in water, but they may be easily converted to themore water-soluble forms by converting the acid to the alkali metal,ammonium, alkylammonium and alkanolammonium salts. In the case of thealkylammonium and alkanolammonium salts, it is preferred that the alkylsubstitutent be of the lower category, i. e., each group having fourcarbon atoms or less. Best results to date have been obtained with thesodium salts. Examples of the halo-hydroxy-phenoxy-aliphatic carboxylicacids are the following or their alkali-metal, ammonium, alkylammoniumor alkanolammonium salts, such as their sodium, potassium,methylammonium, n-butylammonium or diethanolammonium salts:

2-hydroxy-S-iodophenoxyacetic acid 3-hydroxy-6-iodophenoxyacetic acid4-hydroxy-3-iodophenoxyacetic acid 2-hydroxy-3-iodophenoxyacetic acid3-hydroxy-4-iodophenoxyacetic acid 4-hydroxy-3,S-diiodophenoxyaceticacid 2-hydroxy-3,S-diiodophenoxyacetic acid3-hydroxy-4,6-diiodophenoxyacetic acid4-hydroxy-3,S-dibromophenoxyacetic acid2-hydroxy-3,S-dibromophenoxyacetic acid3-hydroxy-4,6-dibromophenoxyacetic acid 2-hydroxy-5-bromophenoxyaceticacid Examples of the halo-hydroxy-phenylamino-aliphatic carboxylic acidsin accordance with my invention are:

2-hydroxy-5-iodophenylglycine 3-hydroxy-G-iodophenylglycine4-hydroxy-3-iodophenylglycine 2-hydroxy-3-iodophenylglycine3-hydroxy-4-iodophenylglycine 4-hydroxy-3,S-diiodophenylglycine2-hydroxy-3,S-diiodophenylglycine 3-hydroxy-4,6-diiodophenylglycine4-hydroxy-3,S-dibromophenylglycine 2-hydroxy-3,5dibromophenylglycine3-hydroxy-4,6-dibromophenylglycine Z-hydroxy-S-bromophenylglycineAppropriate water-soluble salts may be prepared from these acids inaccordance with my invention.

Examples of the amino-hydroxy-phenoxy-aliphatic carboxylic acidsaccording to my invention are:

Z-dimethylaminoS-iodophenoxyacetic acid 3-amino-6-iodophenoxyacetic acid4-diethylamino-3-iodophenoxyacetic acidZ-dimethylamino-3-iodophcnoxyacetic acid 3-amino-4-iodophenoxyaceticacid 4-diethylamino-3,S-diiodophenoxyacetic acid2-amin0-3,S-diiodophenoxyacetic acid3-dimethylamino-4,6-diiodophenoxyacetic acid4-methylamino-3,S-dibromophenoxyacetic acid2-amino-3,5dibromophenoxyacetic acid 3-amino-4,tS-dibromophenoxyaceticacid 2-amin0-5-bromophenoxyacetic acid 3 Appropriate water-soluble saltsof these acids may be prepared by the method described above.

Examples of the amino-halo-phenylamino-aliphatic carboxylic acids inaccordance with my invention are:

Z-dimethylamino-S-iodbphenylglycine 3-ethylamino-6-iodophenylglycine4-amino-3-i0dophenylglycine 2-diethylamino-3-iodophenylglycine3-amino-4-iodophenylglycine 4-methylamino-3,$-diiodophenylglycihe2-dimethyIamino-3,5-diiodophenylglycine 3-dimethylamino-4,6diiodophenylglycine 4-amino-3,5-dibromophenylglycineZ-methylaminoJ-dibrbrhophenylglycine 3-amino-4,6-dibromophenylglycine2-dimethylamino-5-bromophenylglycine Water-soluble: salts of these acidsmay be prepared in accordance with the process described above.

ltwillbe apparentto thoseskilledin the artthatthe acetic acidderivatives in the foregoing examples may be replaced by derivatives ofother acids, such asv the derivatives of propionic, butyric and Valerieacids In some instances i may not be necessary to isolate a particularcompound according to the invention from its isomers. Thus, if in thepreparation.- of. a particular compound isomers are formed, satisfactoryresults may be obtained in some instances by preparing the watersolnblesalts of the mixture of isomers without resorting to extensive:isolation and purification of a single chemical compound of theinvention.

In order more clearly to disclose the nature of the present invention,specific examples illustrating the preparation of typical compounds willhereinafter be described. It should be understood,'however, that this isdone solely by way of' example and is intended neither to delineate thescope of the invention not limit the ambit of the appended claims.

Example 1.3,5-diiodb-2-bydmxyphenoxyacetic' add About 154 grams ofp-hyd'roxyphenoxyacetic acid was added to two liters of a 20% solutionof hydrochloric acid, with stirring. Upon warming the mixture to 78' C.the p-hydroxyphenoxyacetic acid dissolved. The solution was cooled to 45C. and about 290 grams of iodine monochloride was added. After heatingthe mixture on a water bath at about 100 C. for two hours, a smallamount of an aqueous solution of sodium bisulfite was added todecolorize the solution. Upon cooling the solution a precipitate formedwhich was removed by filtration. The filtrate was further concentratedby evaporation which produced a second crop of precipitated crystals.The resulting 3,5-diiodo-2-hydroxyphenoxyacetio acid was found to have amelting point oi about 186-188 C. The neutralization equivalent foundagreed very closely with the theoretical neutralization equivalent,namely, 210.

If it is desired to produce a water-soluble salt of the above acid, suchas the sodium salt, the acid is dissolved in an excess of sodiumhydroxide solution. The salt may be isolated by precipitation with ethylalcohol. Other salts may be prepared by treating the acid with otheralkali-metal hydroxides, such as potassium hydroxide, or with analkylamine, such as diethylamine, or with an alkanolamine, such asdiethanolamine. .Other examples.

of alkylamines which produce the desired salts are ethylamine,diethylamine and isopropylamine. Examples of alkanolamines whichproduced these salts are monoethanolamine and triethanolamine.

Examples 2.2-hydr0xy-5-iod0phenoxyncstic acid 4 added about 250 grams ofiodine monochloride, with stirring, after which the reaction mixture washeated on a water bath for two hours at about C. Upon cooling themixture a precipitate of 2-hydroxy-5-iodophenoxyacetic acid was formed.The precipitated material was further purified by dissolving it in asmall amount of water after heating the water to bring the 2-hydroxy-5-iodophenoxyaoetioaoidiato solution. after which the solution was treatedwith decolon'iing' charcoal. The charcoal west-em by lltn'tiae'and,np'orrcooling the solution, the purified z'hydrmy-i-lodophenoxyace'tieacid crystallized as white needles, having a melting point of -18lf Ce.

Example 3.-2-e'nrixo-6-hd0p frenoxyacetic acid About 167 m o!ortho-aminophenoxyacetic acid was added to a liter of 20% solution ofhydrochloric acid, with stirring. Upon heating the solution, theorthoaminophenoxyeeesie aridtttirsolverlv To missohition was added about1625 grams oiiodl'ne monochloride, with stirring,- after the reactionmixture was heated on a water bath for two hours at about 100"-C. Uponcooling the mixture a precipitate: od'2-amino-iiodophenoxyncetic acidval formed. The precipitated material was further purified by dissolvingit in a small'emount of water after heating the water to bring the2-amino5- iodophenoxyautiemcid into solution, after which the solutionwas treated with decolorizing charcoal. The charcoal'was removedlay-filtration and, upon cooling the solution, the purified$aminoJ-iodophenoxyacetic acid crystalliaed as white needles.

v 1 Example 4 .2-hydrary-5-i0a'op1renylglycine About .166 grams: ofrurtbo-hydroxyphenylglycine was added burn-literati 20% solution athydrochloric acid, with; Uponiheatingthe solution, theortho-hydroxyphmylglycim dissolved. Tothiseolution was added about 162.5:grams of iodine monochloride, with stirring, after which the reactionmixture was heated on a water bath fartwo hours at about. lOO C. Uponcooling the mixture is pmcipitate of Z-hydroxyd-iodophenylglycine wasformed. The precipitated material was further purified: by dissolving itin a small amount of water after heating water to bring theZ-hydroxy-S-iodophenylglycine into solution, after which the solutionwas treated with decol'oring charcoal. The charcoal was removed byfiltration and, upon cooling the solution, the purified 2- hydroxy iiodophenylglycine crystallized as white needles.

The water-soluble products according to the invention may be dispensedas aqueous solutions for use when desired. Alternately, the dry powdermay be packaged under sterile conditions to be converted to awater-soluble preparation at the time of usage by adding a requisiteamount of a solution of a solubilizing agent, such as analkali-hydroxide or an alkylor alkanol-amine.

The terms and expressions which I have employed are used-as terms ofdescription and not of limitation, and 1' have nointentien, in the useof such terms and expressloue, of excluding any equivalents of thefeatures described-in portions thereof, but recognize that variousmodifications are possible within the scope of the invention claimed.

What is'claimed is: t. A compound-of the formula:

X Ir

(om).0oou

whereinxtisamember aelectedfrom thecltiu consisting of hydrogen, iodineand bromine; X: is a member selected iromthe class consisting o! bromineand iodine; Yiesmemherselectedttomtheolauoonrbtlngofthe hydroxyl group,an amino group, monoand dilower alkyl substituted amino groups; Z is theN-H group; n is an integer from 1 to 5; and M is a member selected fromthe class consisting of hydrogen, the alkali-metals, the ammonium group,the alkylammonium and alkanolammonmm groups.

2. A halo-hydroxy-phenylaminoalkyl carboxylic acid; said halogen being amember selected from the class consisting of bromine and iodine and saidalkyl group containing not more than 5 carbon atoms.

3. A water-soluble salt of a halo-hydroxy-phenylaminoalkyl carboxylicacid; said halogen being a member selected from the class consisting ofbromine and iodine and saidalkylponpcontainingnotmorethanScarbon atoms.

4. A compound selected from the class consisting of a halo-phenylglycineha ing one nuclear hydroxyl substituent, an a non-toxic, water-solublesalt thereof; said halogenbeingamemberseiectedfmmtheclassconsisting ofbromine and iodine.

5. A halo-phenylaminoalkyl carboxylic acid having one nuclear hydroxylaubstituent; said halogen being a mem ber selected from the classconsisting of bromine and iodineandsaid alkylgroupcontainingnotmorethanScarbon atoms.

6.Acompoundaccordingtoclaim5inwhichthe halogen is iodine.

7. Lhydroxy-S-iodophenylglycine.

8. A polyiodo-hydroxy-p carboxylic acid; said alkyl group containing notmore than 5 carbon r oms.

9. Halo-hydroxy-phenylglycine; said halogen being a member selected fromthe clas' :onsisting of bromine and iodine.

10. A water-soluble salt of a halo-hydroxy-phenylglycine in which thehalogen is a member selected from the class consisting of bromine andiodine.

11. A halo-amino-phenylglycine; said halogen being a member of the classconsisting of bromine and iodine.

12. A water-soluble salt of a halo-amino-phenylglycine in which thehalogen is a member selected from the class consisting of bromine-andiodine.

References Cited in the tile of this patent UNITED STATES PATENTS2,085,009 Dalmer et a1. June 29, 1937 2,571,515 Archer Oct. 16, 1951FOREIGN PATENTS 514,103 Great Britain Oct. 13, 1939 OTHER REFERENCESBeilstein: Band VI (4th Ed), 1923, pp. 784-5. Longet al.: I. A. C. 8.,vol. 63, pp. 1586-9 (1941). Frieden et al.: I. A. C. 8., vol. 70, p.3511 (1948). Wolfe et aL: J. Org. Chem. 14, 900-1 (1949). Wang: J. Org.Chem. 84, 1271-4 (1951).

Holley: Arch Biochem. Biophys. 35, 171-5 (1952).

1. A COMPOUND OF THE FORMULA: